Farmacocinética populacional pré-clínica e avaliação de segurança de formulação microemulsionada de anfotericina B
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Data
2016-09-16
Autores
Nogueira Filho, Marco Antonio Ferraz [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Depois de quase 50 anos de uso na terapia, a alta potência e amplo espectro de ação asseguram que a anfotericina B (AmB) continue a ser o fármaco de escolha na terapia moderna contra infecções fúngicas invasivas. A AmB está associada a alta incidência de nefrotoxicidade e reações relacionadas à infusão, o que limita a sua utilização e muitas vezes requerem a redução da dose. Novas formulações estão sendo pesquisadas para melhorar as características farmacocinéticas da AmB, levando a novas alternativas de administração, hoje limitada à via intravenosa. No presente estudo, foi avaliado o perfil farmacocinético de um novo sistema microemulsionado de anfotericina B (MEAmB) desenhada por Franzini (2011) por via intravenosa e oral em ratos wistar (n=10), dose de 1mg / kg e 10mg / kg pelas vias intravenosa e oral respectivamente, além da avaliação preliminar de segurança. A formulação apresentou um perfil farmacocinético semelhante à AmB desoxicolato em sua administração intravenosa, sem diferenças significativas tanto nos parâmetros farmacocinéticos quanto na comparação “ponto a ponto”. A MEAmB trouxe ainda diminuição no potencial de nefrotoxicidade, mantendo os níveis de ureia e creatinina inalterados comparando-se pré e pós-exposição enquanto a AmB desoxicolato promoveu aumento significativo dos biomarcadores renais. A MEAmB apresentou uma baixa biodisponibilidade oral (apenas 5,8%) não permitindo os estudos de eficácia planejados para essa formulação. Ainda, através da aplicação da farmacometria, um modelo de farmacocinética populacional foi desenhado e validado para o melhor entendimento entre as covariáveis fisiológicas e ocasionais e a busca de possíveis fatores que impactam a farmacocinética da AmB
After nearly 50 years of use in therapy, high power and broad spectrum of action ensure that amphotericin B (AmB) remains the drug of choice in modern therapy against invasive fungal infections. The AmB is associated with high incidence of nephrotoxicity and infusion-related reactions, which limit their use and often require dose reduction. New formulations are being researched to improve the pharmacokinetic characteristics of AmB, that may lead to new alternative administration routes, limited today only to intravenous administration. In the present study, the pharmacokinetic profile of a new microemulsion system of amphotericin B (MEAmB) formulated by Franzini (2011) for intravenous and oral administration was investigated in wistar rats (n = 10), dose of 1mg / kg and 10mg / kg for intravenous and oral routes respectively, and also a preliminary assessment of safety oral administration. The formulation showed a pharmacokinetic profile similar to AmB deoxycholate in its intravenous administration, no significant differences were found in the pharmacokinetic parameters between the AmB deoxycholate and MEAmB. The MEAmB granted a statistical decrease in the nephrotoxicity potential, keeping urea and creatinine levels unchanged comparing pre- and post-exposure while AmB deoxycholate caused a significant increase in renal biomarkers. The MEAmB showed low oral bioavailability (only 5.8%) not allowing the efficacy studies planned for this formulation. A study of population pharmacokinetic was performed and a population pharmacokinetic model was designed and validated for the better understanding of the physiological and occasional covariates of AmB.
After nearly 50 years of use in therapy, high power and broad spectrum of action ensure that amphotericin B (AmB) remains the drug of choice in modern therapy against invasive fungal infections. The AmB is associated with high incidence of nephrotoxicity and infusion-related reactions, which limit their use and often require dose reduction. New formulations are being researched to improve the pharmacokinetic characteristics of AmB, that may lead to new alternative administration routes, limited today only to intravenous administration. In the present study, the pharmacokinetic profile of a new microemulsion system of amphotericin B (MEAmB) formulated by Franzini (2011) for intravenous and oral administration was investigated in wistar rats (n = 10), dose of 1mg / kg and 10mg / kg for intravenous and oral routes respectively, and also a preliminary assessment of safety oral administration. The formulation showed a pharmacokinetic profile similar to AmB deoxycholate in its intravenous administration, no significant differences were found in the pharmacokinetic parameters between the AmB deoxycholate and MEAmB. The MEAmB granted a statistical decrease in the nephrotoxicity potential, keeping urea and creatinine levels unchanged comparing pre- and post-exposure while AmB deoxycholate caused a significant increase in renal biomarkers. The MEAmB showed low oral bioavailability (only 5.8%) not allowing the efficacy studies planned for this formulation. A study of population pharmacokinetic was performed and a population pharmacokinetic model was designed and validated for the better understanding of the physiological and occasional covariates of AmB.
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Palavras-chave
Farmacocinética Populacional, Anfotericina B, Validação de método, UPLC, Avaliação de Segurança, Farmacometria, Population pharmacokinetics, Amphotericin B, Method validation, UPLC, Safety assessment